Little and largest

What connects a purring cat with Einstein and black holes colliding in deep outer space?…

Little and largest

What connects a purring cat with Einstein and black holes colliding in deep outer space?

It may seem like a silly joke, but Professor Stuart Reid of the University of the West of Scotland (UWS) has an interesting answer – because he has not only played a key role in developing the technology used to confirm one of Einstein's most challenging theories (general relativity), but is also applying it to ground-breaking medical research which may enable scientists to grow human tissue by mechanically vibrating mesenchymal stem cells (MSC) at the nanoscale. And it's all about vibration, whether it's from purring cats or being applied to stem cells, or a giant explosion which sends gravitational waves through the Cosmos, distorting space and time.

Using “nanokicking” to stimulate stem cells is a radical method to grow bone in the lab – a technology which could potentially change the lives of millions of people. But even though it is a brand new technique in medical science, it is based on well-known scientific concepts.

According to one theory, the first sense developed by living cells was the ability to sense mechanical pressure – which is closely related to hearing and touch, and helped these organisms to survive. According to a second theory, cats purr because the vibrations are good for their bodies by helping to heal damaged tissues. And although this may seem rather wacky, “whole body vibration” is already used to help increase bone density and build muscle tone in people who have suffered spinal injuries, as well as to improve the fitness of athletes and speed up recovery from injury. Quite simply, vibration encourages cells to repair damaged bone.

What Reid is working on is not a million miles away from whole body vibration, but what makes his research so different is that he is concerned with vibrating and activating individual cells, the tiny building blocks of the body, at the same time as working as part of the team developing equipment for Advanced LIGO, measuring the largest, most powerful vibrations ever observed in the Cosmos, applying the same technique used in the hunt for gravitational waves to measure and calibrate the tiny vibrations used to nanokick cells.

“In fact,” says Reid, “the tiny signal we send to each stem cell is astronomical compared to the very faint sound from gravitational waves, partly due to the billions of years gravitational waves take to reach us.” And because the laser interferometry technique is so sensitive, it is “relatively easy” to measure what is happening to the stem cells.

This focus on the tiniest and largest of phenomena explains why Reid begins his presentations with an opening slide which shows black holes on one side and stem cells on the other side, to illustrate the different extremes of his work and the fact they're so closely connected.

What connects the black holes and the stem cells is that both emit pressure or waves that detectors are able to sense. Vibrating stem cells encourages them to grow bone, but the key to success is to make sure that the frequency and amplitude of the vibrations are exactly in tune with the stem cells so they can get on with their job, and this requires an instrument to measure and control the vibration – at the nanoscale level.

Reid said in an earlier interview: “If you take one cell and blow it up to the size of a football, then the amount we’re shaking the cells is the same as sliding one sheet of paper in and out from the bottom.” And according to co-inventor Professor Adam Curtis, the so-called nanokicking is more like “the tiniest tickle.”

The solution developed in UWS and the University of Glasgow has since been used successfully by scientists in Nottingham and Galway, without the original team members even needing to be there – proving that the innovative kit can be used “knockdown-style” in other labs with minimal training. Another big attraction, says Reid, is that this new approach needs no fancy chemical “cocktails” or complex and expensive engineering techniques.

In a different area, some of the mirror coating technology developed for the gravitational-wave detectors is also being used for several other applications, including equipment which monitors hospital patients to check if they're dead or alive, by measuring the carbon dioxide exhaled during anaesthesia. The monitors in use today can be confused by nitrous oxide (laughing gas), because it is similar to carbon dioxide, which means it takes longer to check readings and can cause errors. By using special optical filters, however, the new sensor is more accurate and faster. Reid is working in partnership with Cumbernauld-based company Gas Sensing Solutions (GSS) to develop this novel device, and GSS, in turn, will help Reid and his team develop new coatings for the mirrors used in interferometers – the detectors used by LIGO – by growing single-crystal layers which are “structurally perfect” at the atomic level, and thus more sensitive. Reid explains that these “lattice-matched” materials could greatly improve the performance of the next generation of interferometers, and also win new customers for GSS, to make the new production facility more economic to run for everyone involved. The partnership is all about mutual success – Reid and his fellow researchers (including the Institute for Thin Films, Sensors & Imaging at UWS) will help to develop new sensors and upgrade production, while GSS develops a potentially “magic solution,” for astrophysicists and medical researchers.

If at first ....

Reid first got involved with stem cell research when Professor Jim Hough, from the Department of Physics and Astronomy at the University of Glasgow, was asked for help by Professor Adam Curtis of the Institute of Molecular Cell and Systems Biology. One of Reid's colleagues was on holiday that week, so Reid got involved from the start and has not looked back since. In fact, his career has been turned upside down, and he is soon to join the Department of Biomedical Engineering at the University of Strathclyde, focusing on new applications for translational medicine emerging from technology developed for gravitational-wave detection.

The early experiments were not an unqualified success, however, looking at the laser interference patterns projected across petri dishes to measure the effects of different rates and amplitudes of vibration. The technology was not always state-of-the-art – including sticky tape and rulers on computer screens – but the key to success was the combination of expertise used by the team, including physicists such as Reid, who was experienced in similar precision measurement experiments within gravitational-wave research, including computer simulation techniques, and also had a good understanding of mechanical and resonant systems.

The basic idea was that if they could vibrate cell membranes, the cells would respond in particular ways – e.g., secreting minerals. Researchers had already done experiments with cells extracted from mice, but even though the scientific principles appeared well established, in an attempt to “mimic nature,” progress was slow.

“We didn't see any response in the stem cells until we reached about 1,000 Hertz (1,000 vibrations per second),” says Reid. “We were confused at first by this result, because we were initially focused on slower vibration rates similar to that associated with the heart-beat or with walking. We later discovered that bone was optimally piezoelectric (capable of generating voltage), at 971 Hertz, which might explain why we saw the strongest result at 1,000 Hertz.”

The original equipment used was relatively simple, says Reid – with petri dishes (containing cells dispersed in gel) glued to rigid aluminium support disks which were vibrated at different frequencies. Reid’s job is to verify the vibrations by quantifying the frequency and amplitude in order to calculate the forces involved, and enable the researchers to control the vibrations in the bioreactor, so the process can be reproduced precisely again and again.

The project has been so successful that it recently attracted £2.8 million in funding from a charity called “Find a Better Way,” founded by the Manchester United football legend Sir Bobby Charlton to provide help to victims of landmines. Reid says it is already possible “to produce three-dimensional volumes of bone,” but there’s still a long way to go before we can regenerate limbs – and that is the ultimate aim of a new branch of science called “tissue engineering.”

The Find a Better Way project is led by Professor Manuel Salmeron-Sanchez and Professor Matthew Dalby, and includes partners at the Scottish National Blood Transfusion Service (SNBTS). It will develop a novel bone scaffold material, called “HealiOst,” alongside nanokicked bone graft, and will also fund the first in-man trial of nanokicked stem cells within the next 3-4 years.

“Bone is the second most transplanted tissue,” he adds, “and tissue engineering is one of the biggest challenges currently faced within regenerative medicine.”

Turning the tables

According to Reid, “people don’t often think of mechanical transduction” in relation to medical science. Perhaps we’ve missed a trick, he says, by not using more mechanical engineering techniques in biotechnology, and now it's time to change this. “We have under-explored and under-investigated the role of mechanical influences in other areas of science,” he adds.

What Reid will focus on in future research is the use of “highly controlled, reproducible cues to control the behaviour of cells at the nanoscale level,” but Reid is not forgetting astrophysics – this will also lead to the development of innovative solutions which are equally useful in the ongoing quest for gravitational waves.

The major challenge for the astrophysicists is to make sure their detectors can unscramble the signal from gravitational waves from the other noises in the environment (such as earthquakes) and the equipment itself, including the thermally-driven motion of the atoms within the 30 layers of materials, 4.5 microns thick, that form the front surface of the mirrors. Atoms and molecules “jiggle” around at specific temperatures, and the ultimate aim is to eliminate this “thermal noise.” Another major challenge is the way the light is absorbed and scattered by the mirrors, which can also interfere with the signals.

Reid and his research team, along with colleagues at Glasgow, are developing a new kind of dielectric laser mirror coating for the mirrors which involves using microwaves to help deposit silicon atoms on the surface to reduce thermal noise. The ultimate challenge is to make sure the atoms do not land in completely random positions, but arrange themselves in patterns, close to that of a crystal – or what is called an “ideal glass.” The alternative is growing absolutely “perfect” crystals, but Reid says that this is a long-term solution which may require another 10–15 years of research. Meanwhile, the next generation of detectors is being designed and developed, so short-term solutions are also essential to deal with the internal friction which gives rise to the thermal noise observed in the detectors.

“Almost everything wants to move the mirrors more than gravitational waves,” says Reid. The waves may come from a giant explosion 1.3 billion light years away, but even a vibrating stem cell at nanoscale level is louder. And Reid’s future research appears to be heading in both directions at once – Inner Space and Outer Space. “My work in stem cells used to be a spin-off of my work in gravitational waves,” he concludes. “But the tables have turned, and now gravitational-wave research is also, in part, a spin-off of my work in biomedical engineering."

Biography

Professor Stuart Reid, co-Chair of the RSE Young Academy of Scotland, is a Professor of Experimental Physics and Royal Society Industry Fellow working in the Institute of Thin Films, Sensors & Imaging in the School of Engineering and Computing at the University of the West of Scotland. He leads a research team of staff and students who are investigating novel laser mirror coatings for use in future gravitational-waves observatories, focusing on the development of ion-beam sputtering (IBS) and molecular beam epitaxy (MBE), “nanokicking” stem cells in collaboration with Professor Matthew Dalby and Dr Peter Childs of the University of Glasgow, and breath analysis for patient safety during anaesthetic procedures in collaboration with Professor Des Gibson (UWS) and Gas Sensing Solutions Ltd.